Tetralin and indane derivatives and uses thereof

ABSTRACT

Compounds of the formula I:  
                 
 
or pharmaceutically acceptable salts thereof, wherein m, p, q, Ar, R 1  and R 2  are as defined herein. Also provided are methods for preparing, compositions comprising, and methods for using compounds of formula I.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 60/637,836 filed Dec. 21, 2004, thedisclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to substituted indane and tetralin compounds, andassociated compositions, methods for use as therapeutic agents, andmethods of preparation thereof.

BACKGROUND OF THE INVENTION

The actions of 5-hydroxytryptamine (5-HT) as a major modulatoryneurotransmitter in the brain are mediated through a number of receptorfamilies termed 5-HT1, 5-HT2, 5- HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7.Based on a high level of 5-HT6 receptor mRNA in the brain, it has beenstated that the 5-HT6 receptor may play a role in the pathology andtreatment of central nerve system disorders. In particular,5-HT2-selective and 5-HT6 selective ligands have been identified aspotentially useful in the treatment of certain CNS disorders such asParkinson's disease, Huntington's disease, anxiety, depression, manicdepression, psychoses, epilepsy, obsessive compulsive disorders, mooddisorders, migraine, Alzheimer's disease (enhancement of cognitivememory), sleep disorders, feeding disorders such as anorexia, bulimiaand obesity, panic attacks, akathisia, attention deficit hyperactivitydisorder (ADHD), attention deficit disorder (ADD), withdrawal from drugabuse such as cocaine, ethanol, nicotine and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injury such as hydrocephalus. Such compounds are also expected tobe of use in the treatment of certain gastrointestinal (GI) disorderssuch as functional bowel disorder. See for example, B. L. Roth et al.,J. Pharmacol. Exp. Ther., 1994, 268, pages 1403-14120, D. R. Sibley etal., Mol. Pharmacol., 1993, 43, 320-327, A. J. Sleight et al.,Neurotransmission, 1995, 11, 1-5, and A. J. Sleight et al., Serotonin IDResearch Alert, 1997, 2(3), 115-8.

While some 5-HT6 and 5-HT2A modulators have been disclosed, therecontinues to be a need for compounds that are useful for modulating the5-HT6 receptor, the 5-HT2A receptor, or both.

SUMMARY

-   The invention provides compounds of the formula I:-   or a pharmaceutically acceptable salt thereof,-   wherein:

m is from 0 to 3;

p is from 1 to 3;

q is 0, 1 or 2;

Ar is optionally substituted aryl or optionally substituted heteroaryl;

each R¹ is independently halo, alkyl, haloalkyl, heteroalkyl, cyano,—S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c),—N(R^(d))—C(═O)—R^(e), or —C(═O)—R^(e), where t is from 0 to 2, R^(a),R^(b), R^(c), R^(d) and R^(e) each independently is hydrogen or alkyl,and R^(f) is hydrogen, alkyl, alkoxy or hydroxy;

R² is

n and r each independently is 1 or 2; and

X is —NR³ when n is 2, or X is —CHNR⁴R⁵ when n is 1 or 2, wherein R³, R⁴and R⁵ each independently is hydrogen or methyl.

The invention also provides methods for preparing, methods of using, andpharmaceutical compositions comprising the aforementioned compounds.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides substituted quinolinone compounds, associatedcompositions, methods for use as therapeutic agents, and methods ofpreparation thereof. In specific embodiments the invention providespiperazinyl-substituted quinolinone compounds and associatedpharmaceutical compositions, and methods for using the same in thetreatment of central nervous system (CNS) diseases and gastrointestinaltract disorders.

All publications cited in this disclosure are incorporated herein byreference in their entirety.

Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Agonist” refers to a compound that enhances the activity of anothercompound or receptor site.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms (i.e., “C₁-C₆alkyl”). Examples of alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkenylene” means a linear unsaturated divalent hydrocarbon radical oftwo to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms, e.g., ethenylene (—CH═CH—),2,2-dimethylethenylene, propenylene, 2-methylpropenylene, butenylene,pentenylene, and the like.

“Alkoxy” means a group —OR, wherein R is alkyl as defined herein.Examples of alkoxy moieties include, but are not limited to, methoxy,ethoxy, isopropoxy, and the like.

“Antagonist” refers to a compound that diminishes or prevents the actionof another compound or receptor site.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, phenyl, naphthyl, naphthalenyl,phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl,biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl,diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl,benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl,benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl,methylenedioxyphenyl, ethylenedioxyphenyl, and the like, includingpartially hydrogenated derivatives thereof.

“Arylene” means a divalent aryl radical wherein aryl is as definedherein. “Arylene” includes, for example, ortho-, meta- and para-phenylene (1,2-phenylene, 1,3-phenylene and 1,4-phenylene respectively),which may be optionally substituted as defined herein.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical -R-R′ where R is an alkylene group and R′ is an aryl group asdefined herein; e.g., benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Cycloalkyl” means a saturated carbocyclic moiety consisting of mono- orbicyclic rings. Cycloalkyl can optionally be substituted with one ormore substituents, wherein each substituent is independently hydroxy,alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino,unless otherwise specifically indicated. Examples of cycloalkyl moietiesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like, including partially unsaturatedderivatives thereof such as cyclohexenyl, cyclopentenyl, and the like.

“Cycloalkylalkyl” means a moiety of the formula -R-R′, where R isalkylene and R′ is cycloalkyl as defined herein.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, twoor three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independentlyof each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; andwhen n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl,and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl,amino, acylamino, monoalkylamino, or dialkylamino. Representativeexamples include, but are not limited to, methoxy, ethoxy,2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic monovalent radical of 5 to12 ring atoms having at least one aromatic ring containing one, two, orthree ring heteroatoms selected from N, O, or S, the remaining ringatoms being C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl,pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl,pyridinyl, pyridazyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, including partially hydrogenated derivatives thereof. Theaforementioned heteroaryl moieties may be partially saturated. Thus,“heteroaryl” includes “imidazolinyl”, tetrahydropyrimidinyl” and thelike.

“Heteroarylene” means a divalent heteroaryl radical wherein heteroarylis as defined herein. “Heteroarylene” may be optionally substituted asdefined herein. “Heteroarylene” includes, for example, indolylene,pyrimidinylene, and the like.

The terms “halo” and “halogen”, which may be used interchangeably, referto a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, piperidinyl, piperazinyl,homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, pyridinyl, pyridazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl,isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl,tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like, includingpartially unsaturated derivatives thereof.

“Optionally substituted”, when used in association with “aryl”, phenyl”,“heteroaryl”, or “heterocyclyl”, means an aryl, phenyl, heteroaryl, orheterocyclyl which is optionally substituted independently with one tofour substituents, preferably one or two substituents selected fromalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo,nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino,di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR (where R ishydrogen, alkyl, phenyl or phenylalkyl), —(CR′R″)_(n)—COOR (where n isan integer from 0 to 5, R′ and R″ are independently hydrogen or alkyl,and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl orphenylalkyl), or —(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from0 to 5, R′ and R″ are independently hydrogen or alkyl, and R^(a) andR^(b) are, independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease state” means any disease, condition, symptom, or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

acid addition salts formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid,benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid,ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid,glutamic acid, glycolic acid, hydroxynaphtoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, muconic acid,2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinicacid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, andthe like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic or inorganicbase. Acceptable organic bases include diethanolamine, ethanolamine,N-methylglucamine, triethanolamine, tromethamine, and the like.Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

The terms “pro-drug” and “prodrug”, which may be used interchangeablyherein, refer to any compound which releases an active parent drugaccording to formula I in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of formula I are prepared bymodifying one or more functional group(s) present in the compound offormula I in such a way that the modification(s) may be cleaved in vivoto release the parent compound. Prodrugs include compounds of formula Iwherein a hydroxy, amino, or sulfhydryl group in a compound of Formula Iis bonded to any group that may be cleaved in vivo to regenerate thefree hydroxyl, amino, or sulfhydryl group, respectively. Examples ofprodrugs include, but are not limited to, esters (e.g., acetate,formate, and benzoate derivatives), carbamates (e.g.,N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds offormula I, N-acyl derivatives (e.g. N-acetyl) N-Mannich bases, Schiffbases and enaminones of amino functional groups, oximes, acetals, ketalsand enol esters of ketone and aldehyde functional groups in compounds ofFormula I, and the like, see Bundegaard, H. “Design of Prodrugs” p 1-92,Elesevier, N.Y.-Oxford (1985), and the like.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Thoseskilled in the art know how to choose a group for the ease of removaland for the ability to withstand the following reactions.

“Solvates” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgement of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

(i) preventing the disease state, i.e. causing the clinical symptoms ofthe disease state not to develop in a subject that may be exposed to orpredisposed to the disease state, but does not yet experience or displaysymptoms of the disease state.

(ii) inhibiting the disease state, i.e., arresting the development ofthe disease state or its clinical symptoms, or

(iii) relieving the disease state, i.e., causing temporary or permanentregression of the disease state or its clinical symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature.

Chemical structures shown herein were prepared using ISIS® version 2.2.Any open valency appearing on a carbon, oxygen or nitrogen atom in thestructures herein indicates the presence of a hydrogen.

Compounds of the Invention

The invention provides compounds of the formula I:

-   It should be understood that the scope of this invention encompasses    not only the various isomers which may exist but also the various    mixture of isomers which may be formed. Furthermore, the scope of    the present invention also encompasses solvates and salts of    compounds of formula I:-   or a pharmaceutically acceptable salt thereof,-   wherein:

m is from 0 to 3;

p is from 1 to 3;

q is 0, 1 or 2;

Ar is optionally substituted aryl or optionally substituted heteroaryl;

each R¹ is independently halo, alkyl, haloalkyl, heteroalkyl, cyano,—S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c),—N(R^(d))—C(═O)—R^(e), or —C(═O)—R^(e), where t is from 0 to 2, R^(a),R^(b), R^(c), R^(d) and R^(e) each independently is hydrogen or alkyl,and R^(f) is hydrogen, alkyl, alkoxy or hydroxy;

R² is

n and r each independently is 1 or 2; and

X is —NR³ when n is 2, or X is —CHNR⁴R⁵ when n is 1 or 2, wherein R³, R⁴and R⁵ each independently is hydrogen or methyl.

In certain embodiments of formula I, p is 1 or 2, and in specificembodiments p is 2. In many embodiments q is 2. In many embodiments offormula I, n is 2, and in specific embodiments, X is —NR³. In many suchembodiments, r is 1. In certain embodiments of formula I, Ar isoptionally substituted aryl, and more preferably optionally substitutedphenyl. In specific embodiments, R³ is hydrogen., while in otherembodiments R³is methyl.

In certain embodiments of formula I, R² is:

wherein R³, R⁴ and R⁵ are as defined herein.

In certain embodiments of formula I, the subject compounds are morespecifically of formula II:

wherein m, p, Ar, R¹ and R³ are as defined herein.

In certain embodiments of formula II, p is 1 or 2, and more preferably pis 2. In many embodiments of formula II, q is 2. In certain embodimentsof formula II, Ar is optionally substituted aryl, and more preferablyoptionally substituted phenyl. In certain embodiments of formula II, R³is hydrogen, while in other embodiments R³ is methyl.

The compounds of the invention may in certain embodiments be morespecifically of formula IIIa or formula IIIb:

wherein:

s is from 0 to 4;

each R⁶ is independently halo, alkyl, haloalkyl, heteroalkyl, cyano,—S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c),—N(R^(d))—C(═O)—R^(e), or —C(═O)—R^(e), where t is from 0 to 2, R^(a),R^(b), R^(c), R^(d) and R^(e) each independently is hydrogen or alkyl,and R^(f) is hydrogen, alkyl, alkoxy or hydroxy; and

R³ is as defined herein.

In certain embodiments of formula IIIa and formula IIIb, s is from 0 to2, and each R⁶ is independently halo, alkyl, alkoxy, or haloalkyl.

In preferred embodiments, the compounds are of the formula IIIa. In suchembodiments R³ may be hydrogen, or R³ may be methyl. Preferably, s is 0or 1 and R⁶ is halo such as fluoro or chloro.

Where any of R¹, R², R³, R⁴, R^(a), R^(b), R^(c), R^(d), R^(e), andR^(f) herein are alkyl or contain an alkyl moiety, such alkyl ispreferably lower alkyl, i.e. C₁-C₆alkyl, and more preferably C₁-C₄alkyl.

Representative compounds in accordance with the invention are shown inTable 1 together with melting point or mass spectrum M+H, and theexperimental examples (described below) associated with each compound.Melting points in many instances are shown for corresponding additionsalts as indicated in Table 1. TABLE 1 # Structure Name Mp or M + H 1

1-(5-Benzenesulfonyl-indan-1- yl)-piperazine 343 2

1-(5-Benzenesulfonyl-indan-1- yl)-pyrrolidin-3-ylamine 343 3

1-[5-(4-Fluoro-benzenesulfonyl)- indan-1-yl]-piperazine 361 4

1-[5-(2-Fluoro-benzenesulfonyl)- indan-1-yl]-piperazine 361 5

1-[5-(3-Chloro-benzenesulfonyl)- indan-1-yl]-piperazine 378 6

1-[5-(3-Chloro-benzenesulfonyl)- indan-1-yl]-piperidin-4-ylamine 392 7

1-(7-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-piperazine 3578

1-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-piperazine239.3-241.8° C. (HCl salt) 9

1-[6-(4-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-piperazine 375 10

1-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperidin-4-ylamine 371 11

1-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-4-methyl-piperazine 371

Another aspect of the invention provides a composition comprising atherapeutically effective amount of at least one compound of formula (I)and a pharmaceutically acceptable carrier.

Yet another aspect of the invention provides a method for treating acentral nervous system (CNS) disease state in a subject comprisingadministering to the subject a therapeutically effective amount of acompound of formula I. The disease state may comprise, for example,psychoses, schizophrenia, manic depressions, neurological disorders,memory disorders, attention deficit disorder, Parkinson's disease,amyotrophic lateral sclerosis, Alzheimer's disease or Huntington'sdisease.

Still another aspect of the present invention provides a method fortreating a disorder of the gastrointestinal tract in a subjectcomprising administering to the subject a therapeutically effectiveamount of a compound of formula (I).

Another aspect of the present invention provides a method for producinga compound of formula (I).

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 2004, Volumes 1-56. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparecompounds of the invention, wherein X, Ar, m, p, q, n, r, and R¹ are asdefined herein. Numerous synthetic routes to indanes and tetralins areknown and may be used in preparation of the subject compounds, and theprocedure of Scheme A is only exemplary.

In step 1 of Scheme A, ketone compound a is reduced to give acorresponding alcohol compound b. Ketone compound may comprise, forexample, an arylsulfonyl indanone where q is 2 and p 1, an arylsulfonyltetralinone where q is 2 and p is 2, an arylsulfonyl benzoazepinonewhere q is 2 and p is 3, or like ketone in accordance with theinvention. Corresponding, arylsulfanyl (q=0) and arylsulfinyl (q=1)ketone compounds may be used in this step. Ketone compounds a may beprepared by a variety of techniques known in the art, and specificexamples of preparing such compounds are provided below in theExperimental section of this disclosure. The reduction reaction of step1 may be achieved by treatment of ketone compound a with sodiumborohydride under mild protic solvent conditions.

In step 2, alcohol compound b is subject to chlorination to providenitrile chloro compound c. This reaction may be achieved using thionylchloride under non-polar solvent conditions.

An N-alkylation reaction is carried out in step 3 by reaction ofcompound d with chlorine compound c to yield compound e, which is acompound of formula I in accordance with the invention. In compound d Xmay be —NR³ or —CHNR⁴R⁵ where R³, R⁴ and R⁵ each may be hydrogen ormethyl. Where any of R³, R⁴ and R⁵ are hydrogen, suitable protection anddeprotection strategies may be employed in this step.

Many variations on the procedure of Scheme A are possible and will bereadily apparent to those skilled in the art. Specific details forproducing compounds of formula I are described in the Examples sectionbelow.

Utility

The compounds of the invention have selective affinity for 5-HTreceptors, including the 5-HT₆ the 5-HT_(2A) receptor, or both, and assuch are expected to be useful in the treatment of certain CNS disorderssuch as Parkinson's disease, Huntington's disease, anxiety, depression,manic depression, psychosis, epilepsy, obsessive compulsive disorders,mood disorders, migraine, Alzheimer's disease (enhancement of cognitivememory), sleep disorders, feeding disorders such as anorexia, bulimia,and obesity, panic attacks, akathisia, attention deficit hyperactivitydisorder (ADHD), attention deficit disorder (ADD), withdrawal from drugabuse such as cocaine, ethanol, nicotine and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injury such as hydrocephalus. Such compounds are also expected tobe of use in the treatment of certain GI (gastrointestinal) disorderssuch functional bowel disorder and irritable bowel syndrome.

Testing

The pharmacology of the compounds of this invention was determined byart recognized procedures. The in vitro techniques for determining theaffinities of test compounds at the 5-HT6 receptor and the 5-HT2Areceptor in radioligand binding, FLIPR and functional assays aredescribed below.

Administration and Pharmaceutical Composition

The present invention includes pharmaceutical compositions comprising atleast one compound of the present invention, or an individual isomer,racemic or non-racemic mixture of isomers or a pharmaceuticallyacceptable salt or solvate thereof, together with at least onepharmaceutically acceptable carrier, and optionally other therapeuticand/or prophylactic ingredients.

In general, the compounds of the present invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

In general, compounds of the present invention will be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, orparenteral (including intramuscular, intraarterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is generally oral using a convenient daily dosage regimenwhich can be adjusted according to the degree of affliction.

A compound or compounds of the present invention, together with one ormore conventional adjuvants, carriers, or diluents, may be placed intothe form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or pharmaceutically acceptable salts thereof asthe active component. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier may be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatine, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier, providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills,cachets, and lozenges may be as solid forms suitable for oraladministration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described in the Examples below.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Preparation 1 6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme C.

Step 1b 4-(3-Fluoro-phenyl)-4-oxo-butyric acid methyl ester

A solution of 3-fluorobenzaldehyde (35.38 g, 285.07 mml) in 35 mLdimethylformamide (DMF) was added to a heated (48° C.) solution ofmethyl acrylate (26.28 mL, 25.03 g, 290.7 mmol) and powdered KCN underArgon. The reaction mixture was stirred at 40° C. for 2 hours and thenpoured into 500 mL of water. This aqueous phase was extracted twice with500 mL of Et₂O and once with 250 mL of EtOAc. The combined organiclayers were washed with water and saturated brine, and then dried overMgSO₄. The solvent was evaporated under reduced pressure to give 50.89 g(242.2 mmol, 84.93%) of 4-(3-fluoro-phenyl)-4-oxo-butyric acid methylester as an oil. MS: 211 (M+H)⁺.

Step 2

4-(3-Fluoro-phenyl)-butyric acid

A solution of 4-(3-fluoro-phenyl)-4-oxo-butyric acid methyl ester (28.27g, 134.49 mmol), hydrazine monohydrate (26.1 mL, 26.93 g, 537.96 mmol)and KOH (22.64 g, 403.47 mmol) in ethylene glycol (150 mL) was heated toreflux under argon and refluxed for 2 hours. The reaction mixture wascooled and diluted with 1.5 litres of water, 500 mL of Et₂O was added,and the mixtures was acidified by addition of 6 M HCl with stirring,after which an additional 500 mL of Et₂O was added. The organic layerwas removed and the aqueous layer was extracted twice with 250 mL of 500mL of Et₂O/EtOAc (3:1). The combined organic layers were washed withwater, saturated brine, and then dried over MgSO₄. The solvent wasevaporated under reduced pressure to yield a brownish oil, which waseluted through silica gel using hexanes/EtOAc (9:1). Removal of solventunder reduced pressure yielded 18.44 g (101.21 mmol, 75.26%) of4-(3-fluoro-phenyl)-butyric acid as an oil. MS: 183 (M+H)⁺.

Step 3

6-Fluoro-3,4-dihydro-2H-naphthalen-1-one

A solution of methanesulfonic acid (75 mL) and P₂O₅ was stirred at 85°C. for 15 minutes, at which point most of the P₂O₅ had dissolved. Anadditional 15 mL of methanesulfonic acid was added dropwise, and themixture was stirred at 85° C. for 2 hours. The reaction mixture waspoiured into 500 mL of water and extracted twice with 400 mL of EtOAc.The combined organic layers were washed with saturated NaHCO₃, water,and saturated brine, and then dried over MgSO₄. The solvent was removedunder reduced pressure to give an oil that was eluted through silica gelusing hexanes/EtOAc (9:1). Removal of solvent under reduced pressureyielded 6.06 g, 36.91 mmol, 53.97%) of6-fluoro-3,4-dihydro-2H-naphthalen-1-one as a yellow oil. MS: 165(M+H)⁺.

Step 4

6-Phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one

A solution of 6-fluoro-3,4-dihydro-2H-naphthalen-1-one (5.51 g, 33.56mmol), benzenethiol (4.07 g, 3.79 mL, 36.92 mmol) and K₂CO₃ (9.28 g,67.12 mmol) in 50 mL of N-methyl pyrrolidinone (NMP) was heated to 80°C. under argon and stirred at 80° C. for 2 hours. The reaction mixturewas poured int 500 mL of water and diluted with 300 mL of EtOAc. Thelayers were separated and the aqueous layer was extracted twice with 250mL of EtOAc. The combinded organic layers were washed with water,saturated brine, and then dried over MgSO₄. The solvent was removedunder reduced pressure to yield an oil which was eluted through silicagel using hexanes/EtOAc (9:1). Removal of solvent under reduced pressureprovided 8.05 g (31.65 mmol, 94.31%) of6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one as a pale yellow oil.MS: 255 (M+H)⁺.

Step 5

6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one

A solution of 6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one (8.05 g,31.65 mmol) in MeOH/MeCN (50 mL of each) was stirred at roomtemperature. OXONE™ (potassium peroxymonosulfate, 77.83 g, 126.60 mmol)was dissolved in 50 mL of water and was added to the stirring reaction.The reaction mixture was stirred for 15 hours, and then evaporated underreduced pressure. The resulting aqueous residue was diluted with 500 mLof water and extracted three times with 300 mL of EtOAc. The combinedextracts were washed with water, saturated brine, and dried over MgSO₄.The solvent was removed under reduced pressure to yield an oil which waseluted through silica gel with hexane followed by chloroform. Removal ofsolvent under reduced pressure afforded 6.55 g (22.87 mmol, 72.27%) of awhite solid, which was recrystallized from EtO₂/hexanes. MS: 287 (M+H)⁺.

Similarly prepared using the above procedure with 3-chlorobenzenethiolin step 4, was6-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-naphthalen-1-one. MS: 287(M+H)⁺.

Preparation 2 7-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme D.

Step 1:4-(4-Fluoro-phenyl)-4-oxo-butyric acid

Fluorobenzene (50 mL, 530 mmol) and aluminum trichloride (156 g, 1.17mol) were added to 500 mL of methylene chloride, and the reactionmixture was stirred. Succinic anhydride (50 g, 500 mmol) was added tothe stirrring reaction mixture all at once, and the reaction mixture wasstirred at room temperature for 2 hours. The reaction was quenched bycautious addition of 10% HCl, and the reaction mixture was added to 500mL of water. The aqueous mixture was extracted twice with 250 mL ofmethylene chloride, and the combined organic layers were dried (MgSO₄),and evaporated under reduced pressure to give 62 g (316 mmol, 59.6%) of4-(4-fluoro-phenyl)-4-oxo-butyric acid as a crude solid. MS: 197 (M+H)⁺.

Step 2:

4-Oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid

4-(4-Fluoro-phenyl)-4-oxo-butyric acid (10.0 g, 51mmol), thiophenol (5.2g, 51 mmol) and powdered potassium carbonate (13.8 g, 100 mmol) wereadded to 25 mL of dimethyl sulfoxide (DMSO). The reaction mixture washeated to 110° C. for 2 hours, then cooled and diluted by addition of250 mL water. The aqueous mixture was extracted three times with 100 mLof EtOAc, and the combined organic layers were dried (MgSO₄), andevaporated under reduced pressure to yield 11 g (38.5 mmol, 75.5%) of4-oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid as a crude solid. MS: 287(M+H)⁺.

Step 3:

4-(4-Phenylsulfanyl-phenyl)-butyric acid

Powdered Zinc (66 g) was washed with 2% HCl, added to a solution ofHgCl₂ (6 g) in 50 mL of 6M HCl. This mixture was shaken vigorously for 5minutes, and excess liquid was decanted. The mixture was then added to amechanically stirred suspension of4-oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid (6.5 g, 22.7 mmol) in 450mL of 6M HCl, and the reaction mixture was stirred at room temperaturefor 5 days. The mixture was then decanted to remove excess HCl, andquenched by addition of 250 mL water. The aqueous mixture was extractedthree times with 100 mL of EtOAc, and the combined organic layers weredried under reduced pressure to yield 5.0 g (18.4 mmol, 81%) of4-(4-phenylsulfanyl-phenyl)-butyric acid as a crude solid. MS: 273(M+H)⁺.

Step 4:

7-Phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one

4-(4-Phenylsulfanyl-phenyl)-butyric acid (5.0 g, 18.4 mmol) wasdissolved in 50 mL tetrahydrofuran (THF). Oxalyl chloride (1.8 mL, 20mmol) and one drop of DMF were added, and the reaction mixture wasstirred for 1 hour, and then evaporated to dryness under reducedpressure. The resulting residue was dissolved in 40 mL of1,2-dichloroethane, and aluminum trichloride (0.85 g, 25 mmol) was addedall at once. The reaction mixture was stirred for 1 hour, and quenchedby addition of 2% HCl. This aqueous mixture was extracted twice with 100mL of EtOAc, and the combined organic layers were dried (MgSO₄) andevaporated to yield 2.54 g (10 mmol, 55.5%) of7-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one as a gummy residue. MS:255 (M+H)⁺.

Step 5:

7-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one

7-Phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one ( ) was dissolved in 50mL of MeOH and stirred at room temperature. OXONE™ (13.5 g, 22 mmol) wasdissolved in 10 mL of water and added to the stirring reaction. Thereaction mixture was stirred for 8 hours, and then evaporated underreduced pressure. The resulting aqueous residue was diluted with 200 mLof water and extracted three times with 100 mL of EtOAc. The combinedextracts were dried over MgSO₄, and the solvent was removed underreduced pressure to yield an oil which was eluted through silica gelwith 1:1 EtOAc/hexanes. Removal of solvent under reduced pressureafforded 1.7 g (5.9 mmol, 59%) of7-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one as an oil. MS: 287(M+H)⁺.

Similarly prepared using the above procedure with 4-fluorobenzenethiolin step 2, was7-(4-fluoro-benzenesulfonyl)-3,4-dihydro-2H-naphthalen-1-one. MS: 287(M+H)⁺.

Preparation 3 5-Phenylsulfonyl-indan-1-one

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme E.

Step 1:5-Phenylsulfanyl-indan-1-one

5-Fluoro-1-indanone from Aldrich Sigma Chemical Co. (Cat No. 18,566-3)was treated with benzenethiol in the presence of potassium carbonateusing the procedure of step 4 of Example 1 to afford5-phenylsulfanyl-indan-1-one. MS: 241 (M+H)⁺.

Step 2:

5-Phenylsulfonyl-indan-1-one

5-Phenylsulfanyl-indan-1-one was treated with OXONE™ using the procedureof step 5 of Example 1 to afford 5-phenylsulfonyl-indan-1-one. MS: 273(M+H)⁺.

Example 11-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperazine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme E.

Step 16-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ol

6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one (1.31 g, 4.6 mmol) andsodium borohidride (0.35 g, 9.3 mmol) were added to 50 mL methanol, andthe reaction mixture was stirred at room temperature for one hour. Water(200 mL was then added to the reaction mixture, resulting inprecipitation of white crystalls, which were collected by filtration anddried under N₂ to give 1.2 g (4. 16 mmol, 90%) of 6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen- 1-ol, MS: 289 (M+H)⁺.

Step 2

6-Benzenesulfonyl-1-chloro-1,2,3,4-tetrahydro-naphthalene

6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ol (0.65 g, 2.26 mmol)was dissoved in 50 mL toluene, and 1 mL of thionyl chloride was added.The reaction was refluxed for one hour, and then cooled. Solvent wasremoved under reduced pressure to yield6-benzenesulfonyl-1-chloro-1,2,3,4-tetrahydro-naphthalene (0.6 g, 86.3%)as a crude oil. MS: 308 (M+H)⁺.

Step 3

4-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester

6-Benzenesulfonyl-1-chloro-1,2,3,4-tetrahydro-naphthalene (0.6 g, 1.96mmol), piperazine 1-carboxylic acid tert-butyl ester (0.65 g, 3.5 mmol),sodium iodide (0.1 g) and potassium carbonate (0.5 g) were added to 50mL of acetonitrile, and the reaction mixture was refluxed for 120 hours.The reaction mixture was cooled and diluted with 200 mL of water. Theaqueous mix was extracted twice with 200 mL of EtOAc, and the combinedorganic layers were washed with water, brine, and dried over MgSO₄.Solvent was removed under reduced pressure, and the resulting oil waseluted through silica gel (medium pressure chromatography) eluting withEtOAc/Hexanes 20%/80%. Removal of solvent under reduced pressureafforded 0.4 g (0.88 mmol, 45%) of4-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester as an oil. MS: 458 (M+H)⁺.

Step 4

1-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperazine

4-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.4 g, 0.88 mmol) was dissolved in 20 mL oftetrahydrofuran, and 20 mL of 10% HCl in Et₂O was added. The reactionmixture was refluxed for one hour and then cooled. The solvent wasevaporated under reduced pressure, and the resulting solid wasreqcyrstallized from ETOH—Et₂O to yield 0.17 g (0.47 mmol, 53.4%) of1-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperazinee asa hydrochloride salt. MS: 357 (M+H)⁺.

Additional compounds prepared by the procedure of Example 1, using theappropriate tetralinone or indanone starting material in step 1 with theappropriate protected amine in step 3, are shown in Table 1.

Example 2

Formulations

Pharmaceutical preparations for delivery by various routes areformulated as shown in the following Tables. “Active ingredient” or“Active compound” as used in the Tables means one or more of theCompounds of Formula I.

Composition for Oral Administration

Ingredient % wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesiumstearate 0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration

Ingredient % wt./wt. Active ingredient 20.0% Magnesium stearate 0.5%Crosscarmellose sodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidine)1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration

Ingredient Amount Active compound 1.0 g Fumaric acid 0.5 g Sodiumchloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulatedsugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.)1.0 g Flavoring 0.035 ml Colorings 0.5 mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation

Ingredient % wt./wt. Active ingredient 0.25 g Sodium Chloride qs to makeisotonic Water for injection 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation

Ingredient % wt./wt. Active ingredient 1.0% Polyethylene glycol 100074.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Topical Formulation

Ingredients grams Active compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylatedhydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 3

Radioligand Binding Studies

This example illustrates in vitro radioligand binding studies ofcompound of formula I.

The binding activity of compounds of this invention in vitro wasdetermined as follows. Duplicate determinations of 5-HT₆ ligand affinitywere made by competing for binding of [³H]LSD in cell membranes derivedfrom HEK293 cells stably expressing recombinant human 5-HT₆ receptor.Duplicate determinations of 5-HT_(2A) ligand affinity were made bycompeting for binding of [³H]Ketanserin(3-(2-(4-(4-fluorobenzoyl)piperidinol)ethyl)-2,4(1H,3H)-quinazolinedione)in cell membranes derived from CHO-K1 cells stably expressingrecombinant human 5-HT_(2A) receptor. Membranes were prepared from HEK293 cell lines by the method described by Monsma et al., MolecularPharmacology, Vol. 43 pp. 320-327 (1993), and from CHO-K1 cell lines asdescribed by Bonhaus et al., Br J Pharmacol. Jun; 115 (4):622-8 (1995).

For estimation of affinity at the 5-HT₆ receptor, all determinationswere made in assay buffer containing 50 mM Tris-HCl, 10 mM MgSO₄, 0.5 mMEDTA, 1 mM ascorbic acid, pH 7.4 at 37° C., in a 250 microliter reactionvolume. For estimation of affinity at the 5-HT_(2A) receptor alldeterminations were made in assay buffer containing 50 mM Tris-HCl, 5 mMascorbic acid, 4 mM CaCl2, pH 7.4 at 32° C., in a 250 microliterreaction volume.

Assay tubes containing [³H] LSD or [³H]Ketanserin (5 nM), competingligand, and membrane were incubated in a shaking water bath for 75 min.at 37° C. (for 5-HT₆) or 60 min. at 32° C. (for 5-HT_(2A)), filteredonto Packard GF-B plates (pre-soaked with 0.3% PEI) using a Packard 96well cell harvester and washed 3 times in ice cold 50 mM Tris-HCl. Bound[³H] LSD or [³H]Ketanserin were determined as radioactive counts perminute using Packard TopCount.

Displacement of [³H]LSD or [³H]Ketanserin from the binding sites wasquantified by fitting concentration-binding data to a 4-parameterlogistic equation:${binding} = {{basal} + \left( \frac{{B\quad\max} - {basal}}{1 + 10^{- {{Hill}({{\log{\lbrack{ligand}\rbrack}} - {logIC}_{50}}}}} \right)}$where Hill is the Hill slope, [ligand] is the concentration of competingradioligand and IC₅₀ is the concentration of radioligand producinghalf-maximal specific binding of radioligand. The specific bindingwindow is the difference between the Bmax and the basal parameters.

Using the procedures of this Example, compounds of Formula I were testedand found to be selective 5-HT₆ antagonists, selective 5-HT_(2A)antagonists, or both. For example, the compound1-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-4-methyl-piperazineexhibted a pKi of approximately 9.52 for 5-HT₆, and approximately 7.76for 5-HT_(2A).

Example 4

Cognition Enhancement

The cognition-enhancing properties of compounds of the invention may bein a model of animal cognition: the object recognition task model.4-month-old male Wistar rats (Charles River, The Netherlands) were used.Compounds were prepared daily and dissolved in physiological saline andtested at three doses. Administration was always given i.p. (injectionvolume 1 ml/kg) 60 minutes before T1. Scopolamine hydrobromide wasinjected 30 minutes after compound injection. Two equal testing groupswere made of 24 rats and were tested by two experimenters. The testingorder of doses was determined randomly. The experiments were performedusing a double blind protocol. All rats were treated once with each dosecondition. The object recognition test was performed as described byEnnaceur, A., Delacour, J., 1988, A new one-trial test forneurobiological studies of memory in rats. 1: Behavioral data. Behav.Brain Res. 31, 47-59.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: m is from 0 to3; p is from 1 to 3; q is 0, 1 or b 2; Ar is optionally substituted arylor optionally substituted heteroaryl; each R¹ is independently halo,alkyl, haloalkyl, heteroalkyl, cyano, —S(O)_(t)—R^(a),—C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c), —N(R^(d))—C(═O)—R^(e), or—C(═O)—R^(e), where t is from 0 to 2, R^(a), R^(b), R^(c), R^(d) andR^(e) each independently is hydrogen or alkyl, and R^(f) is hydrogen,alkyl, alkoxy or hydroxy; R² is

n and r each independently is 1 or 2; and X is —NR³ when n is 2, or X is—CHNR⁴R⁵ when n is 1 or 2, wherein R³, R⁴ and R⁵ each independently ishydrogen or methyl.
 2. The compound of claim 1, wherein p is 1 or
 2. 3.The compound of claim 2, wherein q is
 2. 4. The compound of claim 6,wherein n is
 2. 5. The compound of claim 3, wherein X is —NR³.
 6. Thecompound of claim 5, wherein r is
 1. 7. The compound of claim 6, whereinAr is optionally substituted aryl.
 8. The compound of claim 7, whereinAr is optionally substituted phenyl.
 9. The compound of claim 8, whereinR³ is hydrogen.
 10. The compound of claim 8, wherein R³ is methyl. 11.The compound of claim 5, wherein R² is:

wherein R³, R⁴ and R⁵ in each independent occurrence is hydrogen ormethyl.
 12. The compound of claim 1, wherein said compound is of formulaII:

and wherein m, p, Ar, R¹ and R³ are as recited in claim
 1. 13. Thecompound of claim 12, wherein p is 1 or
 2. 14. The compound of claim 13,wherein q is
 2. 15. The compound of claim 14, wherein Ar is optionallysubstituted aryl.
 16. The compound of claim 15, wherein Ar is optionallysubstituted phenyl.
 17. The compound of claim 16, wherein R³ ishydrogen.
 18. The compound of claim 16, wherein R³ is methyl.
 19. Thecompound of claim 1, wherein said compound is of formula IIIa or IIIb:

wherein: s is from 0 to 4; each R⁶ is independently halo, alkyl,haloalkyl, heteroalkyl, cyano, —S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c),—SO₂—NR^(b)R^(c), —N(R^(d))—C(═O)—R^(e), or —C(═O)—R^(e), where t isfrom 0 to 2, R^(a), R^(b), R^(c), R^(d) and R^(e) each independently ishydrogen or alkyl, and R^(f) is hydrogen, alkyl, alkoxy or hydroxy; andR³ is as recited in claim
 1. 20. The compound of claim 19, wherein s isfrom 0 to 2, and each R⁶ is independently halo, alkyl, alkoxy, orhaloalkyl.
 21. The compound of claim 19, wherein said compound is of theformula IIIa.
 22. The compound of claim 21, wherein R³ is hydrogen. 23.The compound of claim 21, wherein R³ is methyl.
 24. The compound ofclaim 21, wherein s is 0 or 1 and R⁶ is halo.
 25. The compound of claim1, wherein said compound is selected from:1-(5-Benzenesulfonyl-indan-1-yl)-piperazine;1-(5-Benzenesulfonyl-indan-1-yl)-pyrrolidin-3-ylamine;1-[5-(4-Fluoro-benzenesulfonyl)-indan-1-yl]-piperazine;1-[5-(2-Fluoro-benzenesulfonyl)-indan-1-yl]-piperazine;1-[5-(3-Chloro-benzenesulfonyl)-indan-1-yl]-piperazine; 1-[5-(3-Chloro-benzenesulfonyl)-indan-1-yl]-piperidin-4-ylamine;1-(7-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperazine;1-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperazine;1-[6-(4-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-piperazine;1-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-piperidin-4-ylamine;and1-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-4-methyl-piperazine.26. A pharmaceutical composition comprising an effective amount of thecompound of claim 1 in admixture with a pharmaceutically acceptablecarrier.
 27. A method for treating a central nervous system diseasestate in a subject, said method comprising administering to said subjecta therapeutically effective amount of a compound of claim
 1. 28. Amethod for treating a central nervous system disease state selected frompsychoses, schizophrenia, manic depressions, neurological disorders,memory disorders, attention deficit disorder, Parkinson's disease,amyotrophic lateral sclerosis, Alzheimer's disease, food uptakedisorders, and Huntington's disease, said method comprisingadministering to said subject a therapeutically effective amount of acompound of claim
 1. 29. A method for treating a disorder of thegastrointestinal tract in a subject, said method comprisingadministering to said subject a therapeutically effective amount of acompound of claim 1.